Pathogen Moonlighting Proteins: From Ancestral Key Metabolic Enzymes to Virulence Factors

Abstract

Moonlighting and multitasking proteins refer to proteins with two or more functions performed by a single polypeptide chain. An amazing example of the Gain of Function (GoF) phenomenon of these proteins is that 25% of the moonlighting functions of our Multitasking Proteins Database (MultitaskProtDB-II) are related to pathogen virulence activity. Moreover, they usually have a canonical function belonging to highly conserved ancestral key functions, and their moonlighting functions are often involved in inducing extracellular matrix (ECM) protein remodeling. There are three main questions in the context of moonlighting proteins in pathogen virulence: (A) Why are a high percentage of pathogen moonlighting proteins involved in virulence? (B) Why do most of the canonical functions of these moonlighting proteins belong to primary metabolism? Moreover, why are they common in many pathogen species? (C) How are these different protein sequences and structures able to bind the same set of host ECM protein targets, mainly plasminogen (PLG), and colonize host tissues? By means of an extensive bioinformatics analysis, we suggest answers and approaches to these questions. There are three main ideas derived from the work: first, moonlighting proteins are not good candidates for vaccines. Second, several motifs that might be important in the adhesion to the ECM were identified. Third, an overrepresentation of GO codes related with virulence in moonlighting proteins were seen.

Triosephosphate isomerase of Streptococcus pneumoniae is released extracellularly by autolysis and binds to host plasminogen to promote its activation

“…Proteins that have alternative functions in addition to their main function are called moonlighting proteins [28]. In general, the standard functions of moonlighting proteins are essential for bacterial cell survival and include glycolysis, acting as chaperone proteins, and protein synthesis, and their secondary functions include binding to host epithelial cells, phagocytes, and circulating proteins such as plasminogen [29].…”

Moonlighting on theFasciola hepaticategument: enolase, a glycolytic enzyme, interacts with the extracellular matrix and fibrinolytic system of the host

“…Notably, intracellular enzymes integral to glycolysis (such as enolase) and other conserved metabolic pathways exhibit alternative functions when exposed on the cell surface. This phenomenon is recurrent in pathogenic organisms, where surface-exposed multifunctional proteins facilitate interactions with host tissues and molecules, vital for infection or virulence processes [38,39]. In this study, we aimed to characterize the moonlighting functions of the glycolytic protein enolase from the zoonotic parasitic trematode F. hepatica .…”

A multifunctional enolase mediates cytoadhesion and interaction with host plasminogen and fibronectin in Mycoplasma hyorhinis

“…A fascinating feature of moonlighting proteins is that their moonlighting functions are somewhat similar. The most common interaction partner proteins of hosts are plasminogen and ECM proteins [ 27 ]. Plasminogen is the central component of the fibrinolytic system, a tightly-controlled broad-spectrum proteolytic system.…”